Tacrolimus

(FK506/PROGRAF)

This page describes the Edinburgh regime for the use of the immunosuppressant Tacrolimus.

Current indication

As the lead agent in standard triple therapy for all patients.

Dosage

0.1 mg/kg/day in 2 divided doses (normally between 2 mg and 5 mg bd).

Preparation

Tacrolimus is available as 0.5 mg (cream), 1 mg (white) and 5 mg (greyish red) capsules. The brand is Prograf.

Administration

	Oral route in most instances (well absorbed even in those with NG tubes).
	It is administered usually at 10 am and 10 pm.
	The capsules are taken on an empty stomach either 1 hour before or 2 - 3 hours after meals.
	Contents of the capsule can be suspended in water for NG administration.
	One fifth of the oral dose can be given as a continuous IV infusion in saline via non PVC bags/tubing if absolutely necessary.

Levels

Whole blood trough levels to be checked on Mondays, Wednesdays and Fridays. The target level for the first six months is 10 ng/ml (range 8-12 ng/ml) and 5-10 ng/ml after six months. In adult kidney transplant patients steady state may be reached 2-3 days after starting therapy or changing dose.

Contra-indications

Live vaccines are not to be given to immunosuppressed patients (see vaccinations).

Tacrolimus is contra-indicated in pregnancy. Since it is not known to what extent tacrolimus may influence the efficacy of oral contraceptives it is generally recommended that other forms of contraception be used.

Side Effects

	The most frequent side effects seen with tacrolimus include: abnormal kidney function (similar to Ciclosporin) tremor headache parasthesiae
	Less common side effects are: diarrhoea hypertension hyperglycaemia hyperkalemia hypomagnesaemia visual and neurological disturbances (affected patients should not drive or operate machinery) hypertrophic cardiomyopathy ( in paediatric patients with trough levels >25 mg/ml).

Interactions

Potential interactions due to effects on hepatic microsomal enzymes.

Tacrolimus is extensively metabolised via the hepatic microsomal cytochrome P450 3A4 isoenzyme. Concomitant use of substances known to inhibit or induce cytochrome P450 3A4 (CYP3A4) may affect the metabolism of tacrolimus. Therefore:

• Inhibitors of CYP3A4 may decrease metabolism of tacrolimus and thus increase tacrolimus blood levels, e.g.

• Inducers of CYP3A4 may increase metabolism of tacrolimus and thus decrease blood levels, e.g.

rifampicin

phenobarbitol

phenytoin

(Drugs in red will require a dose adjustment of tacrolimus in nearly all patients. Other listed drugs may require dose adjustment only in individual cases).

• Tacrolimus itself has a powerful inhibitory effect on CYP3A4. Thus concomitant use of tacrolimus with drugs metabolised by CYP3A4 dependant pathways may affect the metabolism of such drugs. For this reason Ciclosporin A should not be co-prescribed with tacrolimus. Patients switched from Ciclosporin to tacrolimus should receive the first tacrolimus dose at least 24 hours after the last Ciclosporin dose.

Interactions due to cumulative toxicity/synergistic effects

• Concurrent use of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the degree of toxicity. Enhanced nephrotoxicity has been observed with co-administration of:

• Cyclosporin A
• Amphotericin B
• Ibuprofen
• Sirolimus (Rapamune)

Hyperkalaemia 

As Tacrolimus may cause hyperkalemia, high potassium intake or potassium sparing diuretics should be avoided.

Interactions due to plasma protein binding of tacrolimus

• Tacrolimus is extensively bound (>98%) to plasma proteins so competition with other highly protein bound drugs may result in displacement of either drug. This displacement may not be reflected in the blood levels of Tacrolimus or other drugs. Therefore, dosage adjustment may not be needed unless clinical signs and symptoms suggest otherwise.

Other interactions

• Vaccinations may be less effective and the use of live attenuated vaccines should be avoided.
• Administration of Tacrolimus with a meal of moderate fat content reduces the oral bioavailability of the drug.
• Complementary medicines may cause a variety of interactions (see more info).

This is not a comprehensive list of potential interactions with tacrolimus. For further information please ask a member of staff or consult the transplant unit pharmacist.

Transplant protocols developed on the Edinburgh Transplant Unit. This page first published March 2002 by Amit Adlakha, reviewed in November 2006 and last modified Tuesday, August 11, 2009.

NOTE that the accuracy of any statements in this information CANNOT be guaranteed. It is published in the belief that it is correct, and we endeavour to keep it so - but we do make mistakes. Furthermore, over some subjects there are differing opinions, or differing degrees of certainty. We have usually not attempted to discuss these here because the aim has been to provide an immediate and brief guide. In all areas, prior medical knowledge is assumed. The EdRenHANDBOOK is not suitable for use by those without such a background. Contact us by email or at the address given at the foot of the contents page with any comments or corrections.